P371: HYPER-CVAD WITH SEQUENTIAL BLINATUMOMAB, WITH OR WITHOUT INOTUZUMAB OZOGAMICIN, IN ADULTS WITH NEWLY DIAGNOSED PHILADELPHIA CHROMOSOME-NEGATIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: N. Short, H. Kantarjian, F. Ravandi, M. Yilmaz, T. Kadia, P. Thompson, X. Huang, M. Konopleva, A. Ferrajoli, N. Jain, K. Sasaki, Y. Alvarado, G. Borthakur, C. Dinardo, M. Ohanian, W. Macaron, S. Kornblau, M. Zhao, M. Kwari, C. Loiselle, R. Delumpa, A. Milton, J. Rivera, S. Lewis, R. Garris, E. Jabbour
Journal: HemaSphere (2022)

Background: Blinatumomab and inotuzumab ozogamicin (INO) are highly effective in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL); blinatumomab is also the only approved therapy for eradication of persistent or recurrent measurable residual disease (MRD) after initial ALL therapy. We hypothesized that early incorporation of blinatumomab and INO in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. Aims: We evaluated the efficacy and safety of hyper-CVAD with sequential blinatumomab, with or without INO, in pts with newly diagnosed Ph-negative B-cell ALL. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight doses of prophylactic IT chemotherapy were given. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Those with high-risk disease features started blinatumomab after 2 cycles of hyper-CVAD. Beginning with pt #39, INO at a dose of 0.3 mg/m2 on day 1 and 8 was added to the 2 cycles of MTX/Ara-C and to 2 cycles of blinatumomab consolidation (4 total cycles with INO). Results: As of February 2022, 58 pts have been treated (38 without INO and 20 with INO). Pt characteristics are summarized in Table 1. Median age was 34 years (range, 17-59 years). 13 pts were in CR at enrollment. Among 45 pts with active disease at study entry, 100% achieved CR, with 80% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 32/42 evaluable pts (76%) after 1 cycle and 55/58 evaluable pts (95%) overall. Two of the 3 pts who did not achieved MRD negativity were later found to have a NUP214::ABL1 fusion. The median duration of follow-up is 26 months (range, 3-61 months). Overall, 5 pts (9%) did not undergo stem cell transplant (SCT) and subsequently relapsed, 18 pts (34%) underwent SCT in first remission (including 2 additional pts who relapsed post-SCT), 2 pts (3%) died in CR, and 33 pts (57%) remain in continuous remission without SCT. All relapses occurred in pts with ≥1 poor-risk feature(s), and no relapses have occurred beyond 2 years from the start of treatment. For the entire cohort, the 3-year continuous remission and OS rates were 84% and 85%, respectively (Figure 1). No relapses or deaths have occurred in the INO group, and the estimated 1-year OS rate is 100%. Treatment was overall well-tolerated. One pt discontinued blinatumomab due to a related adverse event (grade 2 encephalopathy and dysphasia). No pts discontinued INO due to toxicity, and no cases of veno-occlusive disease have been observed. Image:Summary/Conclusion: Hyper-CVAD with sequential blinatumomab, with or without INO, is highly effective as frontline treatment of Ph-negative B-cell ALL, with an overall MRD negativity rate of 95% and a 3-year OS rate of 85%. Early outcomes with the addition of INO to this regimen are encouraging, with no relapses or deaths observed to date.